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At least 19 recordsLinked to original sources
PubMed1988

Antitumor properties of organometallic metallocene complexes of tin and germanium.

The antitumor activity of the four metallocene compounds decaphenylstannocene [eta 5-(C6H5)5C5]2Sn(II), decabenzylstannocene [eta 5-(C6H5CH2)5C5]2Sn(II), decaphenylgermanocene [eta 5-(C6H5)5C5]2Ge(II), and decabenzylgermanocene [eta 5-(C6H5CH2)5C5]2Ge(II), containing the main group IV elements tin or germanium as the central metal atom and two pentasubstituted cyclopentadienyl ring ligands in sandwich arrangement, were tested against Ehrlich ascites tumor in female CF1 mice. The complexes caused cure rates of 40% to 90% of the animals treated over rather broad dose ranges. With both germanocene complexes, no strong dose-activity relationship was manifest. The toxicity of all four metallocenes was low, the LD10 values of both stannocenes being 460 and 500 mg/kg, and those of both germanocenes higher than 700 mg/kg. Regarding the isolated pentasubstituted cyclopentadiene ligands (C6H5)5C5H and (C6H5CH2)5C5H, these also exhibited antitumor activity which was less pronounced than that of the metal-containing sandwich complexes. Decasubstituted stannocene and germanocene compounds represent a new type of non-platinum group metal antitumor agents structurally differing from known inorganic and organometallic cytostatics.

Animals↗
PubMedDate not supplied

[Biochemistry of metallocenes, II. Organ-distribution and thymus affinity of cinnamoyl-[103Ru]ruthenocene (author's transl)].

Metallocenes, labelled with 103Ru, are potential radiopharmaceuticals for use in nuclear medicine diagnosis. Ruthenocene derivatives with oxopropene side-chains were administered to mice and rats to study their biochemical properties. Excretion rates and organ distributions of 103RuCl3 and Cinnamoyl-[103Ru]ruthenocene were very different. While 103RuCl3 was relatively evenly distributed in the body, the metallocene derivative was concentrated in liver, lungs and spleen after intravenous (i.v.) injection. After i.p. injection however a high thymus affinity was observed and autoradiography proved that the site of 103Ru accumulation was in thymocytes. The thymus affinity can be diminished by corticoid pretreatment and raised by inhibition of phagocytosis (BeSO4). The mechanism of accumulation in the thymus and a possible clinical application are discussed.

Animals↗
PubMedDate not supplied

Antitumor metallocenes: new developments and toxicologic features.

Recent results concerning new antitumor metallocene derivatives have shown that not only numerous titanocene dihalides and bis(pseudohalides) exhibit antiproliferative activity, but that also some titanocene complexes (C5H5)2TiX2 containing carboxylates or hydrochlorinated aminothiophenolates as ligands X, are characterized by pronounced antineoplastic efficacy. Whereas antitumor activity of metallocene derivatives has originally been established against Ehrlich ascites tumor, recent experimental results demonstrate antiproliferative activity also against B16 melanoma, sarcoma 180, as well as against human tumors heterotransplanted to athymic mice. Studies upon the organ toxicity of titanocene dichloride indicate a pattern of toxicity markedly differing from that observed after treatment with cytostatic platinum compounds.

Animals↗
PubMed1989

Bifunctional antitumor compounds: interaction of adriamycin with metallocene dichlorides.

In order to synthesize bifunctional antitumor compounds, the interactions of adriamycin with metallocene dichlorides, Cp2MCl2, where M = Zr, Ti, V, have been studied. Using absorption, fluorescence, and circular dichroism measurements, we have shown that adriamycin is able to coordinate to the three metal ions. The interaction of Cp2ZrCl2 and Cp2VCl2 with adriamycin leads to compounds of 1:2 metal:drug stoichiometry, whereas the interaction of Cp2TiCl2 with adriamycin leads to two types of compounds of 1:2 and 1:1 stoichiometry. The Zr-adriamycin complex, which is unable to dissociate, even at a pH lower than 1, does not display antitumor activity against P-388 leukemia. However Ti-adriamycin complexes, which are more susceptible to dissociation in acidic media, exhibit antitumor activity that compares with that of the free drug. These complexes, unlike adriamycin, do not catalyze the flow of electrons from NADH to molecular oxygen through NADH dehydrogenase. In addition, the presence of metal ions promote the binding of the drug to DNA and erythrocyte ghosts.

Animals↗
PubMed1986

Iron-containing metallocenes as active site directed inhibitors of the proteinase that cleaves the NH2-terminal propeptides from type I procollagen.

Derivatives of ferrocene (dicyclopentadienyliron) (Fc) were examined as active site directed inhibitors of type I procollagen N-proteinase, the enzyme that cleaves the NH2-terminal propeptides from type I procollagen. The compounds were shown here to be reversible, competitive inhibitors of the enzyme. The effectiveness of the Fc inhibitors varied with modification of the cyclopentadienyl (cp) rings. The monocarboxylic acid (I) and the 1,1'-dicarboxylic acid (II) derivatives of Fc inhibited 50% of the enzymic activity (I50) at concentrations of 1.0 and 0.5 mM, respectively. The Ki values were 0.3 mM for both I and II. Derivatization of the carbonyl alpha to the cp ring of compound I (FcCOCH2CH2COOH, III) increased the inhibitory activity (I50 = 0.100 mM; Ki = 0.065 mM). Removal of the carbonyl alpha to the cp ring of III did not improve inhibitory activity: FcCH2CH2COOH, I50 = 2 mM; FcCH = CHCOOH, I50 = 1.5 mM. The active inhibitory species apparently contained iron in the 3+ valence state since two ferrocenium derivatives were very effective inhibitors: ferrocenium tetrachloroferrate, IV (I50 = 0.030 mM; Ki = 0.004 mM), and carboxyferrocenium hexafluorophosphate, V (I50 less than 0.1 mM; Ki less than 0.05 mM). In addition, reduction of III with ascorbic acid abolished its inhibitory activity. Compounds I and III stabilized the enzyme to heat denaturation in the absence of exogenous calcium; compound IV did not stabilize the enzyme. Further observations indicated that Fc derivatives were specific inhibitors of procollagen N-proteinase.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1977

[Biochemistry of metallocenes. III. Thymus-affinity for (103Ru)-ruthenocenyl-3-phenyl-propen-1-one].

103Ru labelled 1-Ruthenocenyl-3-phenyl-propen-1-one was administered to mice introperitoneally. The organ distribution was determined in liver, spleen, lung, muscle, blood, kidney and thymus. The highest concentration was found in the thymus-up to 22% of the injected dose/g with corresponding thymus to muscle ratios of up to 364:1. The consequences for nuclear medicine are discussed.

Animals↗
PubMed1986

Organ toxicity of metallocene dichlorides. The effect of (C5H5)2TiCl2 and (C5H5)2VCl2 on renal structure.

The effect of a single application of toxicologically equivalent doses of the cytostatically active metal complexes titanocene dichloride (TDC), vanadocene dichloride (VDC) or cis-diamminedichloroplatinum(II) (DDP) upon the morphologic appearance and the functional behavior of the kidneys was analyzed in mice by use of light and electron microscopy, by determination of blood retention values and by urine analysis. Whereas DDP induced severe structural lesions of the epithelial cells of the proximal and distal tubules as well as profound functional disturbances of the kidneys, the dichlorides of titanium and vanadium caused only slight morphologic alterations such as increased vacuolation in the proximal tubular cells even after administration of LD50 doses; severe pathologic injuries within the kidneys were always lacking. In correspondence to these morphologic findings, no impairment of renal function was detectable after treatment with TDC either in effective or in toxic doses.

Animals↗
PubMed1978

Biochemistry of metallocenes. Identification of the major metabolite of acetylruthenocene.

1. After oral administration of acetylruthenocene to rats, metabolites were detected in bile and urine. 2. The major metabolite, which is present in both bile and urine, is a glucuronide with the structure: C5H5-Ru-C5H4-CO-CH2-O-C6H9O6 3. The metabolite was identified by mass spectrometry of the permethylated glucuronide and mass spectrometry and n.m.r. of the aglycone. 4. The nature of the metabolite is discussed, and a comparison is made with the metabolism of the benzene analogue, acetophenone.

Animals↗
PubMed1986

Design of metallocenic drugs.

Studies on structure-activity relationships of organometallic anticancer drugs are reviewed. Three methods for the development of new structures are described. Drug targeting: platinum complexes with oestrophilic ligands were synthesized, and the endocrine and cytostatic effects are discussed. Quantitative structure-activity relationship determination is presented as a rational method for the design of active compounds. The molecular modelling technique is used for the analysis of molecular properties.

Animals↗
PubMed1989

Antitumor activity of an ionic titanocene tetrachloroferrate derivative against some solid experimental tumors.

The metallocene complex bis(cyclopentadienyl)acetonitrilechlorotitanium(IV) tetrachloroferrate(III) [(C5H5)2Ti(Cl)NCCH3]+[FeCl4]- was investigated for antitumor properties against three solid experimental animal tumors (B16 melanoma, colon 38 adenocarcinoma, Lewis lung carcinosarcoma). The growth of all three tumors was inhibited significantly by the titanocene complex. Colon 38 carcinoma and Lewis lung carcinoma revealed to be more sensitive to the titanocene tetrachloroferrate derivative than solid B16 melanoma, whereby the growth development of the aforementioned tumors was suppressed by 70-76% of control tumor size to T/C ratios amounting to 24-30%. Bis(cyclopentadienyl)acetonitrilechlorotitanium(IV) tetrachloroferrate(III) is representative of ionic titanocene complexes which are generally distinguished by improved water solubility in comparison to neutral metallocene compounds.

Acetonitriles↗
PubMed1991

Two-week, repeated inhalation exposure of F344/N rats and B6C3F1 mice to ferrocene.

Ferrocene (dicyclopentadienyl iron; CAS No. 102-54-5) is a relatively volatile, organometallic compound used as a chemical intermediate, a catalyst, and as an antiknock additive in gasoline. It is of particular interest because of its structural similarities to other metallocenes that have been shown to be carcinogenic. F344/N rats and B6C3F1 mice were exposed to 0, 2.5, 5.0, 10, 20, and 40 mg ferrocene vapor/m3, 6 hr/day for 2 weeks. During these exposures, there were no mortality and no observable clinical signs of ferrocene-related toxicity in any of the animals. At the end of the exposures, male rats exposed to the highest level of ferrocene had decreased body-weight gains relative to the weight gained by filtered air-exposed control rats, while body-weight gains for all groups of both ferrocene- and filtered air-exposed female rats were similar. Male mice exposed to the highest level of ferrocene also had decreased body-weight gains, relative to controls, while female mice had relative decreases in body-weight gains at the three highest exposure levels. Male rats had a slight decrease in relative liver weight at the highest level of exposure, whereas no relative differences in organ weights were seen in female rats. Male mice had exposure-relative decreases in liver and spleen weights, and an increase in thymus weights, relative to controls. For female mice, relative decreases in organ weights were seen for brain, liver, and spleen. No exposure-related gross lesions were seen in any of the rats or mice at necropsy. Histopathological examination was done only on the nasal turbinates, lungs, liver, and spleen.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1985

Ru-labeled ruthenocenoyl-glycine: comparison of clearance with hippuran.

Ruthenocenoyl-glycine (ruppuran) is a metallocene analog of iodo-labeled hippuran. After injection of 103Ru-labeled ruppuran and ruthenocenoyl-1,1'-diglycine in rabbits, measurement with external detectors revealed a very rapid accumulation in the kidneys followed by rapid excretion of the 103Ru activity. By measurement of the radioactivity concentration in plasma and urine samples collected 1-60 min after IV injection, the plasma clearance was calculated and compared with the clearance of 125I-labeled hippuran injected simultaneously. The clearance of ruppuran and ruthenocenoyl-diglycine in rabbits was found to be somewhat higher than that of hippuran. Extrapolating to man (1.73 m3), plasma clearance with both ruthenocene derivatives was approximately 500-600 ml/min. Biochemical data as well as the nuclear properties of 97Ru indicate the usefulness of 97Ru-labeled ruthenocenoyl-glycine as a radiopharmaceutical for kidney function studies.

Animals↗
PubMed1992

Ionic rhenocene derivatives with antitumor activity.

The antitumor activity of the three air-stable bis(cyclopentadienyl)rhenium derivatives [(C5H5)2-ReCl2]+Cl-,[(C5H5)2ReCl2]+[AsF6]- , and [(C5H5)2-ReCl2]+[SbF6]- was tested against Ehrlich ascites tumor in female CF1 mice. All three compounds contain the group-7 transition metal rhenium in the +5 oxidation state as their central metal atom. They are ionic, salt-like complexes that are composed of the cationic [(C5H5)2ReCl2]+ moiety and one of the negatively charged counterions Cl-, AsF6-, or SbF6-. Both the chloro and the hexafluoroarsenate complexes induced a maximal cure rate of 100% when given either in a dose range of 120-160 mg/kg (rhenocene trichloride) or at a single dose of 180 mg/kg (hexafluoroarsenate derivative). The hexafluoroantimonate complex effected a maximal cure rate of only 50% at 60 mg/kg. For the two former compounds, the values for the therapeutic index (TI) amounted to 1.7 and 2.1, respectively. No impairment of the general condition or pathologic symptoms in the viscera could be detected by observation of the animals during the days following treatment with therapeutic doses or by autopsy of the surviving animals on the key date (day 90). The rhenocene derivatives investigated in the present study represent a new class of antitumor metallocene compounds as well as the first rhenium(V) complexes exerting cytostatic activity.

Animals↗
PubMed1992

Antitumor activity of ionic niobocene and molybdenocene complexes in high oxidation states.

Four air-stable niobocene complexes [(C5H5)2NbCl2]+X- with X = BF4, AsF6, SbF6, SO3CF3 and the molybdenocene derivative [(C5H5)2MoCl2]2+[SbF6]2- were investigated for antitumor properties against Ehrlich ascites tumor in female CF1 mice. All compounds are new, salt-like complexes containing a cationic metallocene moiety, where the early transition metals niobium and molybdenum in the high oxidation states +5 and +6 function as central atoms. The niobocene complexes containing tetrafluoroborate (BF4-) or trifluoromethanesulfonate (CF3SO3-) as anions only induced a maximal cure rate of 50% and led to increases in life span of 182% and 178% following application of optimal doses. The other two niobocene compounds with hexafluoroarsenate (AsF6-) and hexafluoroantimonate (SbF6-) as anions and the molybdenocene derivative [(C5H5)2MoCl2]2+[SbF6]2- effected a maximal cure rate of 100% and increases in life span of 346%, 376%, and 332%, respectively, determined on the key date, i.e., on day 90 after transplantation. On applying the niobocene hexafluoroantimonate complex [(C5H5)2NbCl2] +[SbF6]-, the optimal dose range with a cure rate of 100% was rather broad and extended from 20 mg/kg to 40 mg/kg. Correspondingly, the value of the therapeutic index (TI) was high and amounted to 7.2. In the case of the niobocene hexafluoroarsenate and the molybdenocene hexafluoroantimonate complexes, the TI value decreased to 5.3 and 2.6 respectively. Neither impairments of the general condition nor any conspicuous symptoms could be detected after application of therapeutic doses of the five compounds investigated. Compared to the neutral niobocene dichloro complex [(C5H5)2NbCl2], the therapeutic range of the ionic niobocene derivative [(C5H5)2NbCl2]+[SbF6]- was broadened, the TI value markedly elevated from 2.9 to 7.2, and the toxic symptoms were impressively reduced. The niobocene hexafluoroantimonate complex was the most effective compound investigated in the present study.

Animals↗
PubMed1988

Planar chromatographic separation of enantiomers and diastereomers with cyclodextrin mobile phase additives.

A variety of racemic compounds were resolved using reversed-phase thin-layer chromatography (TLC) with mobile phases containing highly concentration solutions of beta-cyclodextrin (beta-CD). These include the drugs labetalol and mephenytoin, metallocenes, crown ethers, methyl-p-toluenesulfinate, nornicotine derivaties and several dansyl and beta-naphthylamide substituted amino acids. It was possible to resolve some racemates that could not be separated on beta-CD bonded phase liquid chromatography (LC) columns with this technique. Likewise there were some compounds that could be resolved with the LC approach that failed to separate with the present TLC method. In cases of racemates that could be resolved by either approach, it was found that the retention order was exactly opposite for the two methods. Enantiomeric resolution is highly dependent on mobile phase composition. In particular, the type and amount of organic modifier as well as the concentration of beta-CD affect the observed resolution. Possible reasons for the chromatographic behavior are discussed. Several diastereoisomeric compounds were separated as well, including steroid epimers and pharmaceutical compounds.

Amino Acids↗
PubMed1988

Photosubstitution of cymantrenylalanine as a tool in peptide chemistry. Synthesis and biological activity of new GnRH analogs.

Beyond its aromatic character and important hydrophobicity, cymantrenylalanine, a metallocenic amino-acid, can be easily photosubstituted with phosphine and phosphite ligands to readily yield new analogs with different hydrophobicity and steric hindrance. The incorporation of phosphine and phosphite ligands is described. As an illustration of the offered possibilities, the synthesis and the biological activity of two new GnRH analogs modified in position 6 are reported.

Alanine↗